Bovine herpesvirus type 1 (BHV-1) is an economically significant pathogen of cattle. BHV-1, which is also known as infectious bovine rhinotracheitis virus, causes severe respiratory infections, conjunctivitis, vulvovaginitis, abortions, encephalitis, and generalized systemic infections. If an animal recovers from a primary infection, the virus remains in the host in a latent state. Reactivation of the virus can be provoked by certain endogenous or exogenous physical modifications in the animal, or experimentally by treatment of the animal with glucocorticoids like dexamethasone.
In an effort to control BHV-1 infections, killed virus and attenuated live-virus vaccines have been developed. While these vaccines appear to induce some level of protection in cattle, the level of immunity is well below the level necessary to afford complete or near-complete protection. For example, the vaccines do not always prevent the establishment of a latent infection by a virulent field strain of BHV-1. Furthermore, the safety of the live-virus vaccines has been questioned. It has been shown recently that two live BHV-1 vaccine strains can be reactivated by the use of dexamethasone, indicating that at least some BHV-1 vaccines can themselves establish a latent infection. See, e.g., Gerber et al. (1978) Am. J. Vet. Res. 39:753-760; Jericho et al. (1983) Can. J. Com. Med. 47:133-139; Pastoret et al. (1980) Infect. Immun. 29:483-488. Despite the recognized need for more efficacious and safer BHV-1 vaccines, no such vaccines have been developed or tested prior to the present invention.
There have been various in vitro studies published regarding the immunology of BHV-1. None of these studies, however, are predictive with regard to the efficacy of any vaccine. For example, Babiuk et al. (1975) Infect. Immun. 12:958-963, is directed to in vitro studies regarding the interaction between BHV-1 and susceptible host cells and the susceptibility of infected host cells to antibody-complement cell lysis. Misra et al. (1981) J. Virol. 40:367-378, reports on the partial characterization of a number of BHV-1 polypeptides and their immunoprecipitation with antiserum. van Drunen Littel-van den Hurk et al. (1984) Virology 135:466-479 and van Drunen Littel-van den Hurk et al. (1985) Virology 144:216-227 are directed to monoclonal antibodies developed against BHV-1 glycoproteins, and the ability of the monoclonal antibodies to neutralize virus and participate in antibody-dependent complement-mediated lysis in vitro. See also Collins et al. (1984) J. Virol. 52:403-409; Okazaki et al. (1986) Virology 150 260-264. van Drunen Littel-van den Hurk et al. (1985) Virology 144:204-215 is directed to the purification of BHV-1 glycoproteins by immunoadsorbent chromatography and the production of antiserum in rabbits. van Drunen Littel-van den Hurk et al. (1986) J. Clin. Microbiol. 23:274-282 is directed to in vitro immunoreactivity of purified BHV-1 glycoproteins and bovine antiserum. Okazaki et al. (1987) Arch. Virol. 92:17-26 is directed to in vitro studies of the reactivities of monoclonal antibodies against BHV-1 glycoproteins with infected cells.
With the exception of purification by electrophoresis or immunoadsorbent chromatography (see references cited above), virus- or cell-free BHV-1 antigens have not been produced. In particular, prior to the present invention, recombinant BHV-1 polypeptides were not available. It was unknown, therefore, whether recombinant polypeptides would be immunologically authentic. Mayfield et al. (1983) J. Virol. 47:259-264 discloses the cloning of a BHV-1 strain and a restriction map. Pachl et al. (1987) J. Virol. 61:315-325, while not directed to BHV-1, discloses the recombinant expression of a glycoprotein from the human pathogen herpes simplex virus type 1. There was no demonstration, however, that the recombinant polypeptide from the human virus is, in fact, protective in a human host. See also PCT Pub. No. W088/02634; U.S. Pat. Nos. 4,661,349; 4,642,333.
Babiuk et al. (1987) Virology 159:57-66 is a partial disclosure of the work leading to the present invention, published after the present invention was made.